Induction of P21-Dependent Senescence: Role of NAE Inhibitor MLN4924

Cellular senescence is a state of cell growth-arrest that limits the proliferation of cancer cells, and thus induction of senescence has been regarded as a promising anticancer strategy. Neddylation is a post-translational modification by adding ubiquitin-like molecule NEDD8 to targeted proteins via an enzymatic cascade reaction, and thus regulates the localization, stability and function of neddylated proteins. The most well identified targets of neddylation so far are cullins which function as essential subunits of multiunit Cullin-RING E3 ubiquitin ligases (CRLs). Recently, a specific inhibitor of NEDD8 activating enzyme (NAE), MLN4924, was identified as the first-in-class anticancer agent. We found that MLN4924 induces cellular senescence as a new mechanism of cancer cell growth suppression. Mechanistically, NAE inhibitor MLN4924 blocks cullin neddylation and thus inhibits the activity of CRL. By doing so, MLN4924 induces the accumulation of p21, a well-known CRL substrate and a major mediator of senescence, to trigger cellular senescence, whereas depletion of p21 largely abrogates MLN4924-induced senescence and attenuates the anticancer efficacy of MLN4924. Our study reveals a novel mechanism of MLN4924 action which will facilitate the development of this investigational drug as a novel class of anticancer agent.